The story of living in spite of melanoma, CLND (X 2!), metastasis, vaccines, anti-PD-1, lung removal, and stereotactic radiation. (With a little adenocarcinoma ex-goblet cell carcinoid thrown in!!!) The story of life with family and friends. {Posts under ~ Sew Chaotically, Travel Chaotically, and Chaotic Cookery also housed within! A girl's gotta have fun!}

About Me

Who am I? That is a question the rest of you could probably answer better than I. I am a wife, mother, daughter, sister, friend, pediatric nurse practitioner, cook, teacher, gardener, lover of words and music, occasional seamstress, and homemaker. I do have a couple of talents of questionable merit: I can create a decent meal in less than 30 minutes. I can feed and/or soothe almost any baby. And I can remember practically any song I've ever heard. For the rest, I'd rather those who know me decide.

Thursday, March 27, 2014

Anti-PDL1 for melanoma: A Phase 1 trial of MEDI4736 in Combination With Dabrafenib and Trametinib or With Trametinib Alone

A Phase 1 Open-label Study of Safety and Tolerability of MEDI4736 in
Combination With Dabrafenib and Trametinib or With Trametinib Alone NCT02027961

The study above is now recruiting. You can see all the details on ClinicalTrials.gov by entering the NCT#. Some folks on the forums are asking questions about it so I thought I could try to answer a few points here.

Dabrafenib (Tafinlar) is a BRAF inhibitor that achieves a 70-80% response rate in melanoma patients with the BRAF v600E mutation. Its down sides include the fact that the response can come with some nasty side effects and it can cease working for many melanoma patients in 6-9 months, though there are some out there who have done great for years. (You know you're the man Dick K!!!) Trametinib (Mekinist) is a downstream inhibitor in the same pathway as the BRAF inhibitors. The good news is that it seems to work in patients with NRAS mutations as well as those having the BRAF v600E mutation. Recently the combo of these drugs was approved and is helping patients get rid of their tumors with fewer side effects and with less chance of melanoma learning how to work around the drugs. (I have posts on Jan 13, 2013 and more recently on Feb 13, 2014 with more information on these drugs.)

MEDI4736 is an anti-PDL1 drug produced by MedImmune. Anti-PDL1 is an antibody that blocks a switch on a melanoma cell that turns off your immune system. Anti-PD1 drugs, are antibodies that block the switch on the white cells so that they can attack melanoma.

As someone who (along with most of the folks
in my BMS anti-PD1 (Nivo) study at Moffitt) has had my tumor tested for
the expression of PD-L1 on its surface...I have a very specific interest
in the intel coming out about the anti-PDL1 drugs. Back in 2012, The New England Journal of Medicine
noted that in patients from a Nivo study, with a variety of tumor
types, 25 of the 42 patients tested had tumors that were positive for
PD-L1. "Of these 25 patients, 9 had an objective response. NONE of
the 17 patients with PD-L1 NEGATIVE tumors had an objective response."
NOW...with that said....since then I have been told by the folks
at Moffitt that that data was really important AND also told that it
didn't mean so much after all. We have still NOT been told what our
personal tumors tested out to be...nor have I seen a report on that
data.
_______________________________________________
To back up a step here is a basic info report on a different anti-PDL1 product: Promising drug prevents cancer cells from shutting down immune system
31 May 2013 19:19:03 yale.edu"An investigational drug that targets the immune system’s ability to
fight cancer is showing promising results in Yale Cancer Center (YCC)
patients with a variety of advanced or metastatic forms of the disease.
Updated data from this Phase 1 clinical trial are being formally
presented at the 2013 annual meeting of the American Society of Clinical
Oncology (ASCO) in Chicago. Yale Cancer Center is one of the lead trial sites. The abstract was made public by ASCO in advance of the meeting. The drug, known as MPDL3280A and manufactured by Roche Genentech, is designed
to prevent a cancer cell’s mutated and overexpressed PD-L1 gene protein
from putting the immune system to sleep. The overexpressed PD-L1
protein turns off the immune system’s T-cells by binding to its PD-1 and
B7.1 proteins. In doing so, it disguises itself and evades detection
and destruction by the body’s immune response.This new drug is the latest advance in the burgeoning field of
immunotherapy, which aims to boost the body’s immune system to fight
the foreign pathogens of cancer. By blocking the cancer tumor’s PD-L1
protein, MPDL3280A frees the immune system to do its job. This PD-L1
targeted antibody was specially engineered to increase safety and
efficacy over earlier immunotherapy agents. Yale oncologists report that the efficacy of MPDL3280A was
evaluated in 140 patients with locally advanced or metastatic solid
tumors who had exhausted other means of therapy. Tumor shrinkage was
observed in patients with non-small cell lung cancer, melanoma, kidney
cancer, colorectal cancer, and gastric cancer. Yale oncologists say
ongoing, durable responses were observed in nearly all patients who
responded to the drug. Overall, 29 out of 140 patients (21
percent) experienced significant tumor shrinkage, and the highest number
of responses were in patients with lung cancer and melanoma.MPDL3280A was generally well tolerated, they say, with few
immune-related adverse events. Some patients were continuing to respond
more than a year after starting treatment.“We have been very impressed by the response in seriously ill
patients whose cancer had metastasized. So far, almost none of those who
showed tumor shrinkage have gotten worse, which is extraordinary,”
said lead author Roy Herbst, M.D., professor of medicine and chief of
medical oncology at Yale Cancer Center and Smilow Cancer Hospital at
Yale-New Haven. “Immunotherapy treatment is providing new hope for
cancer patients,” he added."
_______________________________________________
Currently there is a Phase 2 study ongoing, using anti-PDL1 with
avastin in renal cell carcinoma. There is also a Phase 3 study in
progess using anti-PDL1 in patients with non-small cell lung cancer.
Neither of these studies have published outcomes thus far...to my
knowledge.
________________________________________________
From ASCO, 2013: A study of MPDL3280A (engineered
anti-PDL1): Activity, safety, and characterization of immune response
in pre- and on-treatment tumors in metastatic melanoma patients. Sosman, Hamid, Lawrense, Flaherty, Hodi, et al."Melanoma tumor cells may utilize PD-L1 overexpression to escape
immune surveillance...In Phase 1 study, metastatic melanoma patients
received MPDL3280A IV every 3 weeks for up to 1 year and had tumor
assessments every 6 weeks. As of Feb 2013, 44...patients dosed at
0.1-20mg/kg were evaluated...61% received >/= 1 prior systemic
regimen and 36% received prior immunotherapy. 14% of patients
experienced grade 3/4 treatment related adverse events, including
[elevated liver enzymes]. No grade 3-5 pneumonitis or colitis was
reported. 38...patients...dosed at 1-20mg/kg prior to August 2012 were
evaluable...An objective response rate of 32% (11/34) was observed in
patients with cutaneous, mucosal or unknown primary histology (0/4
ocular patients responded). Resection of remaining mass in a responding
patient after 1 year of therapy showed no evidence of viable tumor.
Responses were durable, with 10/11 ongoing (responding patients on study
for 3-10.5 months). Analysis of archival tumor samples showed that
PD-L1 positive patients had a higher rate of disease control versus
PD-L1 negative patients [87% vs 20%]."
_________________________________________________
Clearly, as there is no data out on the combo this clinical trial is examining (to my knowledge) I don't have any intel to add that addresses that specifically. But, for those of you with interest in the trial and its components....perhaps this background information will be helpful.
Wishing you all my best - c

3 comments:

I bet you get comments on years old posts all the time. A caregiver who posts on behalf of her father on the bladder cancer advocacy network site recently broke the news that he has been pulled out of the same Nivolumab trial that I am in. His liver mets have been unaffected in the trial and he's had what dr believes is some non-pseudo progression. Fortunately, our principal trial dr (a hematologist/oncologist), had sent off a liver met biopsy to Foundation One. There they determined the cancer cells actually were positive for BRAF mutations (not V600e). Mekinist alone was recommended. An application to a a company called Novartis was granted and her father will be given a hopeful regimen of this drug. I'm very hopeful and encouraged that this has all sprouted from an immunology trial, and the my (our) doc is using resources to try and find an inhibitor that matches her fathers mets. If this works for him in any way, it's an example of modern target therapy in action. Mekinist for BC due to the presence of BRAF is a new one to me but I am optimisticOf course, solid information on Mekinist and its history were as available and well-explained on your blog as anyplace out there. You're awesome!

It is very interesting and hopeful as these cancers reveal their overlap. Hopefully treatments and cures will do the same. Hope MEK serves this patient well!!! Glad my post was of some help via an explanation at least.